果糖與葉酸對腺嘌呤誘發腎損傷小鼠腎功能的影響

Abstract

已知高含糖飲料低蔬果攝取的飲食型態，可能導致慢性腎病盛行率上升。近年來，研究指出腺嘌呤可作為誘發小鼠腎損傷的媒介。故本研究以腺嘌呤誘發腎損傷小鼠探討果糖與葉酸對腎功能的影響。首先建立腺嘌呤誘發腎損傷小鼠模式，將28週齡的C57BL/6雄鼠分為 (1)正常飲食組 (Ctrl)、低劑量組 (0.1% ade)以及高劑量組 (0.15% ade)，餵飼六週後結果顯示，ade兩組都能顯著增加腎功損傷指標，而0.1% ade組體重下降幅度較低，故選擇0.1% 腺嘌呤進行後續實驗。首先探討果糖與葉酸不足對腎功能的影響，將7週齡的C57BL/6雄鼠分為 (1)正常飲食組 (Ctrl)、(2)高果糖組 (Hfru(ade))、(3)高果糖腺嘌呤組 (Hfru +ade)、和 (4)高果糖缺葉酸腺嘌呤組 (Hfru-f +ade)。小鼠22週齡開始添加0.1% (w/w) 腺嘌呤誘發腎損傷，44週齡犧牲分析腎功能指標。結果顯示，不論高果糖組或腺嘌呤 (+ade) 組的飲水量與血清尿素氮、血清肌酸酐、尿蛋白、腎纖維化區域和免疫細胞浸潤顯著增加，Hfru-f +ade組的尿腎損傷分子-1 (KIM-1)較高。顯示葉酸不足加劇腎損傷。接著，為探討純果糖與葉酸補充對腎功能的影響，8週齡的C57BL/6雄鼠分為 (1)正常飲食組 (Ctrl)、(2)高果糖組 (Hfru)、(3)正常飲食腺嘌呤組 (Ctrl +ade)、(4)高果糖腺嘌呤組 (Hfru +ade)、(5)高果糖低葉酸腺嘌呤組 (Hfru-f +ade)以及 (6)高果糖葉酸補充腺嘌呤組 (Hfru+f10+ade)。小鼠18週齡添加0.1%~0.2% (w/w) 腺嘌呤誘發腎損傷，25週齡時犧牲。結果顯示，高果糖組 (Hfru) 體重與肝脂肪比控制組顯著較高，Hfru-f +ade組腎功能顯著降低，而補充葉酸顯著降低血清肌酸酐。綜上所述，高果糖會增加肝脂肪堆積造成肥胖，葉酸不足加劇腎損傷，葉酸補充能減緩腎臟損傷。

Dietary patterns high in sugary beverages and low in fruits and vegetables have been linked to the increasing prevalence of chronic kidney disease. Recent studies have identified adenine as a mediator that induces kidney injury in mice. This study investigates the effects of fructose and folate on renal function in adenine-induced kidney injury murine model.First, we established a mouse model of adenine-induced kidney injury. 28week-old male C57BL/6 mice were divided into three groups: (1) normal diet (Ctrl), (2) low-dose adenine (0.1% ade), and (3) high-dose adenine (0.15% ade). After 6 weeks, both adenine groups showed significant increases in kidney injury markers, with less weight loss in the 0.1% ade group. Therefore, 0.1% adenine was chosen for subsequent experiments. To explore the effects of fructose and folate deficiency on renal function, 7 week-old male C57BL/6 mice were divided into four groups: (1) normal diet (Ctrl), (2) high fructose (Hfru(ade)), (3) high fructose with adenine (Hfru +ade), and (4) high fructose with folate insufficiency and adenine (Hfru-f +ade). From the age of 22 weeks, the mice were treat with 0.1% (w/w) adenine to induce kidney injury, and were sacrificed at 44 weeks of age for analysis. The results showed that both Hfru and ade groups showed significantly increased water intake, serum urea nitrogen, serum creatinine, urinary protein, renal fibrosis areas, and immune cell infiltration. The Hfru-f +ade group had higher levels of urinary kidney injury molecule-1 (KIM-1), indicating that folate deficiency exacerbates kidney damage. To further investigate the impact of fructose and folate supplementation on renal function, 8 week-old male C57BL/6 mice were divided into six groups: (1) normal diet (Ctrl), (2) high fructose (Hfru), (3) normal diet with adenine (Ctrl +ade), (4) high fructose with adenine (Hfru +ade), (5) high fructose with low folate with adenine (Hfru-f +ade), and (6) high fructose with folate supplementation with adenine (Hfru+f10+ade). From the age of 18 weeks, the mice were treat with 0.1~0.2% (w/w) adenine to induce kidney injury, and were sacrificed at 25 weeks of age for analysis. The results showed that the Hfru group had significantly higher body weight and liver fat compared to the control group. The Hfru-f +ade group exhibited significantly reduced renal function, while Hfru+f10+ade significantly lowered serum creatinine levels.These results demonstrated that high fructose increases liver fat accumulation. Low folate exacerbates kidney damage by increasing fibrosis, while folate supplementation can mitigate kidney injury.